Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In a serious case, arrhythmias give rise to a ventricular fibrillation and can cause sudden death.
Though various antiarrythmic agents are now available on the market, those, having both satisfactory effects and high safety, have not been obtained. For example, antiarrythmic agents of Class I according to the classification of Vaughan-Williams which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV respectively, have a defect that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
Antiarrythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Drugs in this class are limited. Examples such as sotalol and amiodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which may cause cardiac depression and be contraindicated in certain susceptible patients. Also, amiodarone is severly limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillations. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.
A number of antiarrhythmic agents have been reported in the literature, such as those disclosed in:
(1) EP 397,121-A, PA1 (2) EP 300,908-A, PA1 (3) EP 307,121, PA1 (4) U.S. Pat. No. 4,629,739, PA1 (5) U.S. Pat. No. 4,544,654, PA1 (6) U.S. Pat. No. 4,788,196, PA1 (7) EP application 88302597.5, PA1 (8) EP application 88302598.3, PA1 (9) EP application 88302270.9, PA1 (10) EP application 88302600.7, PA1 (11) EP application 88302599.1, PA1 (12) EP application 88300962.3, PA1 (13) EP application 235,752, PA1 (14) DE 3633977-A1, PA1 (15) U.S. Pat. No. 4,804,662, PA1 (16) U.S. Pat. No. 4,797,401, PA1 (17) U.S. Pat. No. 4,806,555, PA1 (18) U.S. Pat. No. 4,806,536. PA1 1) benzo, PA1 2) thieno, PA1 3) furo, and PA1 4) pyrido; PA1 a) hydrogen, or PA1 b) C.sub.1-6 alkyl; PA1 a) hydrogen, PA1 b) C.sub.1-6 alkyl, PA1 c) (CH.sub.2).sub.n --C.sub.6 H.sub.4 --R.sup.10, wherein R.sup.10 is PA1 d) --CO--C.sub.1-6 alkyl, or PA1 e) --CO--C.sub.6 H.sub.4 --R.sup.10 ; PA1 f) --COO--C.sub.1-6 alkyl, or PA1 g) --CONR.sup.4 R.sup.5 ; PA1 a) hydrogen, PA1 b) C.sub.1-6 alkyl, unsubstituted or substituted with --(CR.sup.4 R.sup.5).sub.n --(CR.sup.4 R.sup.5).sub.g --R.sup.11, wherein g is 1-5, and R.sup.11 is PA1 c) --CO--C.sub.1-6 alkyl, unsubstituted or substituted with PA1 d) --CO--C.sub.6 H.sub.4 --R.sup.10, or PA1 e) R.sup.7 and R.sup.8 taken together with the nitrogen atom to which they are attached represent a 5 or 6 membered saturated heterocyclic ring, unsubstituted or substituted with oxygen or hydroxy, which may contain an additional heteroatom selected from N, S(O).sub.n or 0, such as pyrrolidine, morpholine, piperidine, pyrrolidinone, piperidinone, piperazine or N-methylpiperazine; PA1 a) hydrogen, or PA1 1) --H, PA1 2) --OH, PA1 3) --O(C.sub.1-6 alkyl), PA1 4) --CN, PA1 5) --NHSO.sub.2 C.sub.1-6 alkyl, PA1 6) --COOH, PA1 7) --COOC.sub.1-6 alkyl, PA1 8) --CONR.sup.12 R.sup.13, wherein R.sup.12 and R.sup.13 are independently PA1 9) --NR.sup.12 R.sup.13, PA1 10) halo, PA1 12) C.sub.5-8 cycloalkane, PA1 13) C.sub.5-8 cycloalkene, or PA1 14) ##STR4## wherein s is 1-3 and the R.sup.3 groups may be the same or different; PA1 R.sup.4 and R.sup.5 are as defined above, PA1 m and q are independently 0-5, PA1 Q is a bond, --O--, C.dbd.O, CHOH, N--R.sup.5 or --S(O).sub.n --, with the proviso that if Q is --O--, N--R.sup.5 or --S(O).sub.n --, m is other than 0 or 1, and the further proviso that if Q is --O--, N--R.sup.5 or --S(O).sub.n --, and M is any functional group connected through a heteroatom, q is other than 0 or 1, and with the proviso that when n and q are both O and Q is a bond (making R a bond), M is other than --H; PA1 1) hydrogen, PA1 2) C.sub.1-6 alkyl, either unsubstituted or substituted with PA1 3) --OH, PA1 4) C.sub.1-3 alkoxy, either unsubstituted or substituted with C.sub.1-3 alkoxy, PA1 5) --N(R.sup.5)SO.sub.2 (C.sub.1-6 alkyl), PA1 6) --N(R.sup.5)SO.sub.2 (CH.sub.2).sub.g CO.sub.2 H, PA1 7) --N(R.sup.5)SO.sub.2 (CH.sub.2).sub.g CO.sub.2 C.sub.1-6 alkyl, PA1 8) --NO.sub.2, PA1 9) --N(R.sup.5)COC.sub.1-6 alkyl, PA1 10) --N(R.sup.5)SO.sub.2 --C.sub.6 H.sub.4 --R.sup.4, PA1 11) --N(R.sup.5)CO--C.sub.6 H.sub.4 --R.sup.4, PA1 12) --NR.sup.4 R.sup.5, PA1 13) halo, PA1 14) --CO--C.sub.1-6 alkyl, PA1 15) --CONR.sup.12 R.sup.13, PA1 16) --CN, PA1 17) --CO.sub.2 R.sup.5, PA1 18) --C(R.sup.5).dbd.N--OR.sup.9, PA1 19) benzoyl, either unsubstituted or substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo, or hydroxy, PA1 20) --N(R.sup.5)COO(C.sub.1-6 alkyl), PA1 21) --N(R.sup.5)COO-phenyl either unsubstituted or substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy or halo, PA1 22) --N(R.sup.5)CONR.sup.4 R.sup.5, PA1 23) --S(O).sub.n C.sub.1-6 alkyl, PA1 24) --S(O).sub.n --C.sub.6 H.sub.4 --R.sup.4, PA1 25) --CF.sub.3, PA1 26) phenyl, either unsubstituted or substituted with C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo or hydroxy, PA1 27) imidazolyl, PA1 28) --SO.sub.2 NR.sup.12 R.sup.13, PA1 29) --N[S(O).sub.2 C.sub.1-6 alkyl][(CH.sub.2).sub.p CN], wherein p is 2-5, PA1 30) --N(R.sup.5)--C(NR.sup.4 R.sup.5).dbd.N--CN, PA1 31) --N(R.sup.5)--C(SR.sup.5).dbd.N--CN, or PA1 1) benzene, PA1 2) pyridine, PA1 3) benzofuran, PA1 4) quinoline, PA1 5) benzofurazan, PA1 6) benzofurazan-N-oxide, PA1 7) benzimidazole, PA1 8) indole, PA1 9) indoline, PA1 10) benzothiafurazan, PA1 11) benzothiafurazan-N-oxide, PA1 12) 1,3-dihydro-2,1,3-benzothiadiazole, PA1 13) 1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide, PA1 14) 1,3-dihydro-2H-benzimidazole-2-one, PA1 15) 2,1-benzisoxazole, PA1 16) quinoxaline, PA1 17) 1,2-benzisoxazole, PA1 18) indane, PA1 19) tetralin, PA1 20) benzocycloheptane, PA1 21) benzodioxane, PA1 22) 1,3-benzodioxole, PA1 23) imidazole, PA1 24) naphthalene, PA1 25) benzocyclobutane, PA1 26) thiophene, PA1 27) thiazole, PA1 28) phthalimide, PA1 29) pyrimidine, PA1 30) imidazolidin-2-one, PA1 31) furan, PA1 32) pyridine-N-oxide, PA1 33) pyridone, PA1 34) indolin-2-one, PA1 35) tetrazolopyridine, PA1 36) 2,3-dihydrobenzofuran, PA1 37) benzomorpholine, PA1 38) isoquinoline, PA1 39) pyrimidindione, PA1 40) N,N-di(C.sub.1-6 alkyl)pyrimidindione, PA1 40) benzothiophene, PA1 41) pyrazine, and PA1 42) pyridazine; PA1 a) --NO.sub.2, PA1 b) --NHSO.sub.2 (C.sub.1-6 alkyl), PA1 c) --SO.sub.2 (C.sub.1-6 alkyl), PA1 d) --NHSO.sub.2 --C.sub.6 H.sub.4 --R.sup.4, PA1 e) --SO.sub.2 --C.sub.6 H.sub.4 --R.sup.4, PA1 f) hydrogen, or PA1 a) --OH, PA1 b) --CN, or PA1 c) --(Ar.sup.2)--(R.sup.3).sub.s, wherein Ar.sup.2 is: PA1 and wherein s is 1 or 2, and R.sup.3 is:
Compounds of similar structure are found in Japanese patent publication 88-63533-B of Daiichi Pharmaceutical Co.; J. Med. Chem., 19, 1315 (1976) by Bauer et al; Iorio et al in Il. Farmaco-Ed Sci., 32, 212-219 (1977): Houlihan et al, U.S. Pat. No. 3,686,186; Davis et al, U.S. Pat. No. 4,420,485; Kealey, U.S. Pat. No. 4,810,792; Parham et al, J. Org. Chem., 41 2629 (1976). None of the compounds disclosed in the foregoing references are alleged to have antiarrhythmic activity.
Now with the present invention, there is provided a new use as antiarrhythmic agent for many of these known compounds and a group of new compounds of similar structure with an increased degree of activity.